Method for prophylaxis and treatment of diabetic complications with 4[alpha-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid and derivatives

ABSTRACT

The present invention relates to an agent for the prophylaxis and treatment of diabetic complications comprising, as an active ingredient, 4-[α-hydroxy-2-methyl-5(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid, an optically active compound thereof or a pharmaceutically acceptable salt thereof. The present invention further relates to a method for the prophylaxis and treatment of diabetic complications comprising administering an effective amount of this compound. The medicament of the present invention is useful for the prophylas and treatment of diabetic complications, namely, diabetic neuropathy, nephropathy, ophthalmopathy, arteriosclerosis and the like. The action of the drug is long-lasting for very small doses and a single administration a day is sufficient

TECHNICAL FIELD

[0001] This is a divisional of Ser. No. 09/091,993, filed Jun. 26, 1998,which is a 371 of PCT/JP96/03776, filed Dec. 24, 1996.

[0002] The present invention relates to an agent for the prophylaxis andtreatment of diabetic complications, namely, to an agent for theprophylaxis and treatment of diabetic neuropathy, nephropathy,ophthalmopathy and arteriosclerosis. More particularly, the presentinvention relates to an agent for the prophylaxis and treatment ofdiabetic complications comprising, as an active ingredient,4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5dimethylbenzoic acid,an optically active compound thereof or a pharmaceutically acceptablesalt thereof. The present invention further relates to a method for theprophylaxis and treatment of diabetic complications.

BACKGROUND ART

[0003] The discovery of insulin and its clinical application resulted indrastic progress in the treatment of diabetes. Life sustention of thepatients with diabetes—which had been a deadly disease until then—wasstrikingly improved. However, the therapy of chronic complications ofdiabetes has become a new problem.

[0004] The therapy of diabetes aims at prevention of such chroniccomplications, and practical consists of a further control of bloodglucose and a direct therapy of complications. The major chroniccomplications of diabetes are known to be neuropathy, nephropathy,ophthalmopathy, arteriosclerosis and the Eke David M. et al., N. Engl.J. Med., 328, p.1676-1685(1993)).

[0005] Various factors have been considered to be responsible for theonset and progression of chronic complications of diabetes. For example,there are known an abnormal sorbitol metabolism theory wherein activitypromotion of sorbitol-producing polyol metabolitic pathway is the cause(Gabbay K. H. et al., N. Engl. J. Med. 288, p.831-837(1973)), acirculatory disorder theory wherein causative factor is a decreasedblood flow due to angiopathy (Dyck P. J. et. al., Proc. Natl. Acad. Sci.USA, 82, p.2513-2517 (1985)), a theory attributing the disease to acompound produced by non-enzymatic binding reaction of protein andreducing glucose (AGE:advanced glycation endproduct) (Brownlee M. etal., N. Engl. J. Med. 318, p. 1315-1321 (1988)) and the like. Based oneach hypothesis, an aldose reductase inhibitor and lipoprostaglandin Elhave been developed, and an AGE production inhibitor is underdevelopment

[0006] The diabetic patients show promoted platelet aggregation, and themechanism thereof has been known to be the promotion of biosynthesis ofthromboxane (hereinafter abbreviated as TX) A2 due to hyperglycemia.This is considered to be one of the pathogens of diabetic chroniccomplications (Giovanni Davi M. D. et al., N. Engl. J. Med. 322,p.1769-1774 (1990)). Thus, lipoprostaglandin E1 (hereinafter sometimesto be referred to as Lipo PGE1) having peripheral circulation improvingaction or platelet aggregation inhibitory action,6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl(cilostazol) and6[4-(R)-chlorophenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl)-5-(Z)-hexenoicacid.hydrochloride (investigational numer: KDI-792) having TXA2 receptorantagonistic/synthesis inhibitory activity have been under developmentas agents for the prophylaxis and treatment of diabetic complications.

[0007] On the other hand, Japanese Patent Examined Publication No.41143/1993 discloses4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acidhaving pharmacological activities such as strong TXA2 biosynthesisinhibitory activity, platelet aggregation inhibitory action,vasodilating action and the like, which is useful for the prophylaxisand treatment of thrombosis, cerebral hemorrhage, myocardial infarction,acute cardiac death, angina pectoris, hypertension, asthma, naphritisand the like, an optically active compound and a pharmaceuticallyacceptable salt thereof. Nevertheless, it is not known that thesecompounds act as agents for the prophylaxis and treatment of diabeticcomplications.

[0008] Under the circumstances, the development of a new therapeuticagent that acts directly on chronic complications of diabetes for theprophylaxis and treatment of diabetes, which is capable of providing abetter quality of life has been desired.

[0009] The Lipo PGE 1, cilostazol, KDI-792 and the like, which are underdevelopment as agents for the prophylaxis and treatment of diabeticcomplications based on the above-mentioned peripheral circulationimproving activity, platelet aggregation inhibitory activity and TXA2receptor antagonistic/synthesis inhibitory activity, all exhibit only ashort duration of activity and require 2 to 3 times of administration aday. Considering the quality of life of the patients with diabetes, theyare remotely sufficient.

[0010] The present inventors have confirmed that sodium ozagrel [sodium(E)-p-(imidazol-1-ylmethyl)cinnamate] having TXA2 synthesis inhibitoryactivity suppresses promotion of biosynthesis of TXA2 in rats withdiabetes, but does not improve decreased tail nerve conduction velocity.This suggests that not every TXA2 synthesis inhibitor is effective fordiabetic complications.

DISCLOSURE OF THE INVENTION

[0011] The present inventors have conducted intensive studies from thisviewpoint and found that4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl-3,5-dimethylbenzoic acid,an optically active compound thereof and a pharmaceutically acceptablesalt thereof, having pharmacological activities of TXA2 biosynthesisinhibitory activity, platelet aggregation inhibitory activity andvasodilating action, are useful for the prophylaxis and treatment ofdiabetic complications, namely, for the prophylaxis and treatment ofdiabetic neuropathy, nephropathy, ophthalmopathy and arteriosclerosis,and that the activity thereof is long-lasting for small doses, thusenabling a single administration a day, which resulted in the completionof the present invention.

[0012] Accordingly, the present invention provides the following.

[0013] 1) An agent for the prophylaxis and treatment of diabeticcomplications, comprising4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid,an optically active compound or a pharmaceutically acceptable saltthereof as an active ingredient.

[0014] 2) An agent for the prophylaxis and treatment of diabeticcomplications, comprising sodium4-[α-hydroxy-2-methyl-(1-imidazolyl)benzyl-3,5-dimethylbenzoatedihydrate as an active ingredient.

[0015] 3) An agent for the prophylaxis and treatment of diabeticcomplications, comprising(S)−(−)4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid or a pharmaceutically acceptable salt thereof as an activeingredient.

[0016] 4) An agent for the prophylaxis and treatment of diabeticcomplications, comprising sodium(S)−(−)-4-[α-hydroxy-2-methyl-5(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate as an active ingredient.

[0017] 5) The agent for the prophylaxis and treatment of the above 1) to4), wherein the diabetic complication is at least one member selectedfrom the group consisting of neuropathy, nephropathy, ophthalmopathy andarteriosclerosis.

[0018] 6) The agent for the prophylaxis and treatment of the above 1) to4), wherein the diabetic complication is neuropathy.

[0019] 7) The agent for the prophylaxis and treatment of the above 1) to4), wherein the diabetic complication is nephropathy.

[0020] 8) The agent for the prophylaxis and treatment of the above 1) to4), wherein the diabetic complication is ophthalmopathy.

[0021] 9) The agent for the prophylaxis and treatment of the above 1) to4), wherein the diabetic complication is arteriosclerosis.

[0022] 10) A method for the prophylaxis and treatment of diabeticcomplications, comprising administering an effective amount of4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid,an optically active compound thereof or a pharmaceutically acceptablesalt thereof.

[0023] 11) A method for the prophylaxis and treatment of diabeticcomplications, comprising administering an effective amount of sodium4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-diethylbenzoatedihydrate.

[0024] 12) A method for the prophylaxis and treatment of diabeticcomplications, comprising administering an effective amount of(S)−(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid or a pharmaceutically acceptable salt thereof.

[0025] 13) A method for the prophylaxis and treatment of diabeticcomplications, comprising administering an effective amount of sodium(S)-(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-diethylbenzoate2/3 hydrate.

[0026] 14) The method of any one of the above 10) to 13) wherein thediabetic complication is at least one member selected from the groupconsisting of neuropathy, nephropathy, ophthalmopathy andarteriosclerosis.

[0027] 15) The method of any one of the above 10) to 13) wherein thediabetic complication is neuropathy.

[0028] 16) The method of any one of the above 10) to 13) wherein thediabetic complication is nephropathy.

[0029] 17) The method of any one of the above 10) to 13) wherein thediabetic complication is ophthalmopathy.

[0030] 18) The method of any one of the above 10) to 13) wherein thediabetic complication is arteriosclerosis.

[0031] 19) Use of4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid,an optically active compound thereof or a pharmaceutically acceptablesalt thereof for the production of a medicament for the prophylaxis andtreatment of diabetic complications.

[0032] 20) Use of sodium4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl-3,5-dimethylbenzoatedihydrate for the production of a medicament for the prophylaxis andtreatment of diabetic complications.

[0033] 21) Use of(S)-(−)-4-α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid or a pharmaceutically acceptable salt thereof for the production ofa medicament for the production of a medicament for the prophylaxis andtreatment of diabetic complications.

[0034] 22) Use of sodium(S)-(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate for the production of a medicament for the prophylaxis andtreatment of diabetic complications.

[0035] 23) The use of any one of the above 19) to 22) wherein thediabetic complication is at least one member selected from the groupconsisting of neuropathy, nephropathy, ophthalmopathy andarteriosclerosis.

[0036] 24) The use of any one of the above 19) to 22) wherein thediabetic complication is neuropathy.

[0037] 25) The use of any one of the above 19) to 22) wherein thediabetic complication is nephropathy.

[0038] 26) The use of any one of the above 19) to 22) wherein thediabetic complication is ophthalmopathy.

[0039] 27) The use of any one of the above 19) to 22) wherein thediabetic complication is arteriosclerosis.

[0040] 28) A pharmaceutical composition for the prophylaxis andtreatment of diabetic complications, which comprises an effective amountof 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid, an optically active compound thereof or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

[0041] 29) A pharmaceutical composition for the prophylaxis andtreatment of diabetic complications, which comprises an effective amountof sodium4-]α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoatedihydrate and a pharmaceutically acceptable carrier.

[0042] 30) A pharmaceutical composition for the prophylaxis andtreatment of diabetic complications, which comprises an effective amountof (S)-(−)4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-ethylbenzoicacid or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

[0043] 31) A pharmaceutical composition for the prophylaxis andtreatment of diabetic complications, which comprises an effective amountof sodium(S)-(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate and a pharmaceutically acceptable carrier.

[0044] 32) The pharmaceutical composition of any one of the above 28) to31) wherein the diabetic complication is at least one member selectedfrom the group consisting of neuropathy, nephropathy, ophthalmopathy andarteriosclerosis.

[0045] 33) The pharmaceutical composition of any one of the above 28) to31) wherein the diabetic complication is neuropathy.

[0046] 34) The pharmaceutical composition of any one of the above 28) to31) wherein the diabetic complication is nephropathy.

[0047] 35) The pharmaceutical composition of any one of the above 28) to31) wherein the diabetic complication is ophthalmopathy.

[0048] 36) The pharmaceutical composition of any one of the above 28) to31) wherein the diabetic complication is arteriosclerosis.

[0049] 37) A commercial package comprising the pharmaceuticalcomposition of any one of the above 28) to 31) and a written matterassociated therewith, the written matter stating that saidpharmaceutical composition can or should be used for the prophylaxis andtreatment of diabetic complications.

DETAILED DESCRIPTION OF THE INVENTION

[0050] The action as the agent for the prophylaxis and treatment ofdiabetic complications of the present invention, namely, the action asthe agent for the prophylaxis and treatment of neuropathy, nephropathy,ophthalmopathy and arteriosclerosis, can be confirmed through rat tailnerve conduction velocity, sciatic nerve conduction velocity, degree ofglomerular disorder, amount of urinary albumin excretion, degree ofcataract examining funduscopy, degree of hypertrophy and the like.

[0051] Of the diabetic complications in the present invention,neuropathy means symmetric polyneuropathy of sensory, motor andautonomic nerves, and local or polydomous neuropathy of cerebral nerve;and ophthalmopathy means cataract, glaucoma, retinopathy, iritis and thelike.

[0052] The compounds of the present invention can be synthesized by themethods described in Japanese Patent Examined Publication No. 41143/1993and Japanese Patent Unexamined Publication No. 215771/1990.

[0053] The pharmaceutically acceptable salts of the compounds of thepresent invention include, for example, salts with inorganic acid suchas hydrochloric acid, hydrobromic acid and sulfuric acid; acid additionsalts with organic acid such as fumaric acid, maleic acid, mandelicacid, citric acid, tartaric acid, salicylic acid and the like; saltswith metal such as sodium, potassium, lithium, calcium, magnesium, zincand aluminum and salts with amino acid such as lysine. Further,hydrates, such as 1/2 hydrate, 1/3 hydrate, 2/3 hydrate, monohydrate,3/2 hydrate and dihydrate, are also encompassed.

[0054] Preferable compounds of the present invention include sodium4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoatedihydrate (hereinafter sometimes referred to as compound A-1), sodium(S)-(−)-4[α-hydroxy-2-methyl-5(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate (hereinafter sometimes referred to as compound A-2), sodiumR-(+)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate (hereinafter sometimes referred to as compound A-3),(S)−(−)-4[-α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid hereinafter sometimes referred to as compound A4), and(R)-(+)-4-[α-hydroxy-2-methyl-5(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid (hereinafter sometimes referred to as compound A-5). Compound A-1is crystals having a melting point of 271-285° C. Compound A-2 has anoptical rotation of [α]_(D) ²³⁵−149.5° (c=1.0, water), an opticalrotation of compound A-3 is [α]_(D) ²⁴+147.2° (c=1.0, water) andcompound A-4 has a melting point of 286-288° C. (decomposition) and anoptical rotation of [α]_(D) ²¹−261.5° (c=1.0, dimethylformamide), andcompound A-5 has a melting point of 286-287° C. (decomposition) and anoptical rotation of [α]_(D) ²¹+260.5° (c=1.0, dimethylformamide).

[0055] The agent for the prophylaxis and treatment of diabeticcomplications according to the present invention is formulated as ageneral pharmaceutical preparation. For example, the compound of thepresent invention is formulated into a dosage form suitable for oral orparenteral administration; such as a pharmaceutical composition ortablet, pill, powder, granule, capsule, troche, syrup, liquid, emulsion,suspension, injection (liquid, suspension), suppository, inhalant,percutaneous absorber, eye drop, eye ointment and the like, which isproduced by admixing the compound with a pharmaceutically acceptablecarrier (e.g., excipient, binder, disintegrator, corrective, corrigent,emulsifier, diluent, solubilizer and the like). When a solid preparationis prepared, an additive is used, such as sucrose, lactose, cellulose,D-mannitol, maltitol, dextran, starch, agar, arginates, chitins,chitosans, pectin, tragacanth gums, gum arabic, gelatins, collagens,casein, albumin, calcium phosphate, sorbitol, glycine,carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose,hydroxypropylmethylcellulose, glycerol, polyethylene glycol, sodiumhydrogencarbonate, magnesium stearate, talc and the like. Wherenecessary, tablets are prepared to have an ordinary tablet coating togive, for example, sugar-coated tablet, enteric-coated tablet,film-coated tablet or two-layer tablet or multi-layer tablet.

[0056] When a semi-solid preparation is to be produced, animal and plantfats and oils (e.g., olive oil, corn oil, castor oil and the like),mineral oil and fats (e.g., petrolatum, white petrolatum, solid paraffinand the like), wax (e.g., jojoba oil, carnauba wax, yellow bees wax andthe like), partially synthesized or entirely synthesized glycerol fattyacid ester (e.g., lauric acid ester, myristic acid ester, palmitic acidester and the like) and the like are used. Examples of commerciallyavailable products thereof include Witepsol (manufactured by DynamiteNovel), Pharmasol (manufactured by NOF Corporation) and the like.

[0057] When a liquid preparation is to be produced, an additive such assodium chloride, sorbitol, glycerol, olive oil, propylene glycol, ethylalcohol and the like is used. Particularly when an injection is to beproduced, a sterile aqueous solution (e.g., physiological saline andisotonic solution) or oily liquid (e.g., sesame oil and soy bean oil) isused. Where necessary, an adequate suspending agent (e.g., sodiumcarboxymethylcellulose), non-ionic surfactant, solubilizer (e.g., benzylbenzoate and benzyl alcohol) and the like may be also used. When an eyedrop is to be produced, an aqueous liquid or aqueous solution is used,which is particularly a sterile aqueous solution for injection. This eyedrop liquid may contain various additives as appropriate, such as buffer(preferably, borate buffer, acetate buffer, carbonate buffer and thelike are used for reducing irritation), isotonizing agent, solubilizer,preservative, thickener, chelating agent, pH adjusting agent(preferably, pH is generally adjusted to about 6-8.5), aromatic and thelike.

[0058] The amount of the active ingredient of these preparation is0.1-100 wt %, suitably 1-50 wt %, of the preparation. The dose variesdepending on the symptom, body weight, age and the like of patients. Inthe case of oral administration, the dose is generally about 0.01-50mg/kg body weight/day for an adult, which is preferably administered ina single dose or several doses.

EXAMPLES

[0059] The agent for the prophylaxis and treatment of diabeticcomplications of the present invention is explained more specifically byway of Formulation Examples and pharmacological activity. It should benoted that the present invention is not limited to theseexemplifications.

Formulation Example 1

[0060] Film-coated Tablet Compound A-1 50.0 mg D-mannitol 70.5 mg Cornstarch 16.0 mg Sodium hydrogencarbonate 15.0 mgHydroxypropylmethylcellulose  3.0 mg Talc  5.0 mg Magnesium stearate 0.5 mg

[0061] Compound A-1, D-mannitol, corn starch and sodiumhydrogencarbonate were mixed and an aqueous solution ofhydrorypropylmethylcellulose was sprayed for flow granulation. Thegranules were passed through a 24-mesh sieve, and talc and magnesiumstearate were added. The mixture was processed in a rotary compressor(Kikusui Seisakusho) to give tablets each weighing 160 mg. Then, a filmcoating agent comprising hydroxypropylmethylcellulose as a film coatingbase was applied at 6 mg per tablet

Formulation Example 2

[0062] Fine Granules Compound A-1   10% D-mannitol 89.5%Hydroxypropylcellulose  0.5%

[0063] Compound A-1 and D-mannitol were mixed and an aqueous solution ofhydroxypropylcellulose was added. The mix e was kneaded, which wasfollowed by granulation and drying at 50° C. The granules were passedrough a 32-mesh sieve to give fine granules.

Formulation Example 3

[0064] Tablets Compound A-1 50.0 mg D-mannitol 30.0 mg Corn starch 19.0mg Sodium hydrogencarbonate 15.0 mg Hydroxypropylmethylcellulose  1.5 mgTalc  4.0 mg Magnesium stearate  0.5 mg

[0065] Compound A-1, D-mannitol, corn starch and sodiumhydrogencarbonate were mixed and an aqueous solution ofhydroxypropylmethylcellulose was sprayed for flow granulation. Thegranules were passed through a 24-mesh sieve, and talc and magnesiumstearate were added. The mixture was processed in a rotary compressorKikusui Seisakusho) to give tablets each weighing 120 mg.

Formulation Example 4

[0066] Fine Granules Compound A-2  5% D-mannitol 92%Hydroxymethylpropylcellulose  3%

[0067] Compound A-2 and D-mannitol were mixed and an aqueous solution ofhydroxypropylmethylcellulose was added. The mixture was kneaded, whichwas followed by granulation and drying at 50° C. The granules werepassed through a 32-mesh sieve to give fine granules.

[0068] The pharmacological activity of the pharmaceutical agent of thepresent invention is explained by way of Experimental Examples.

Experimental Example 1

[0069] Diabetes was induced by intravenous administration ofstreptozotocin (65 mg/kg) to 6-week-old male Sprague-Dawley rats.Starting from 2-4 weeks after the onset of diabetes, a 0.5%hydroxypropylmethylcellulose suspension containing the compound of thepresent invention was orally administered once a day. At 4-7 weeks fromthe administration, tail nerve conduction velocity was measured with aninduction potential test device (Neuropack 2, manufactured by NihonKohden) according to a modification of the method of Miyoshi (FukuokaMedical Journal, vol. 62, pp. 588-403 (1971)). To be specific,subcutaneous temperature at the tail was maintained at 37° C. and thetail nerve was percutaneously stimulated electrically at 2 stimulationpoints (interval 6 cm). The distance between stimulation points wasdivided by the difference between latencies in electromyogram induced togive nerve conduction velocity. As to the test group in Table 1, bloodglucose was measured at 6 weeks after administration. At 7 weeks afteradministration, urinary excretion of TXB2, which is a stable metaboliteof TXA2, was measured. TABLE 1 urinary TXB2 tail nerve conductionexcretion velocity m/sec dose blood glucose mg/day/100 g 7 wks aftertest group mg/kg/day mg/dl body weight administration Control group 0 122.0 ± 3.8** 4.1 ± 0.4** 44.6 ± 0.5** Diabetes group 0 870.3 ± 78.516.9 ± 1.7   41.3 ± 0.5  Compound A-1 0.03 718.3 ± 50.7 10.6 ± 1.4** 42.0 ± 0.5  Administered group Compound A-1 0.1 772.1 ± 32.4 6.9 ± 0.8**43.4 ± 0.4** Administered group Compound A-1 0.3 791.9 ± 65.5 5.1 ±0.5** 43.7 ± 0.3** Administered group Compound A-1 1.0 718.4 ± 64.1 3.4± 0.3** 44.8 ± 0.4** Administered group

[0070] The data was shown by mean standard error of 11-12 rats pergroup. Each group was compared to diabetes group by Dunnett's test(**P<0.01).

[0071] From the above-mentioned results of Experimental Example, thecompound A-1 of the present invention decreased urinary TXB2 excretionthat had been increased by diabetes, and increased tail nerve conductionvelocity which had been decreased by diabetes, in a dose-dependentmanner without affecting the blood glucose. TABLE 2 dose tail nerveconduction velocity test group mg/kg/day m/sec 5 wks afteradministration Control group 0 43.7 ± 0.4** Diabetes group 0 39.4 ± 0.2 Compound A-2 0.03 40.7 ± 0.5** Administered group Compound A-2 0.1 42.6± 0.4** Administered group Compound A-2 0.3 43.0 ± 0.3** Administeredgroup Compound A-2 1 42.6 ± 0.5** Administered group

[0072] The data was shown by mean±standard error of 10 rats per group.Each group was compared to diabetes group by Dunnett's test (**P<0.01).TABLE 3 dose tail nerve conduction velocity test group mg/kg/day m/sec 4wks after administration Control group 0 43.0 ± 0.5  Diabetes group 038.8 ± 0.5  Compound A-4 0.3 40.9 ± 0.5** Administered group CompoundA-4 1 41.3 ± 0.4** Administered group Compound A-4 3 41.7 ± 0.5**Administered group

[0073] The data was shown by mean standard error of 10 rats per group.Each group administered with the compound was compared to diabetes groupby Dunnett's test (**P<0.01).

[0074] From the above-mentioned results of Experimental Examples, thecompound A-2 and compound A-4 of the present invention suppresseddecrease in tail nerve conduction velocity in a dose-dependent manner.

Experimental Example 2

[0075] A 0.5% hydroxypropylmethylcellulose suspension containing thecompound of the present invention was orally administered to 9-week-oldmale spontaneously diabetic mice (db/db) once a day. At 4-5 weeks fromthe administration, sciatic nerve conduction velocity was measured withan induction potential test device (Neuropack 2, manufactured by NihonKohden) according to a modification of the method of Yasuda (Diabetes,38, p. 832-838 (1989)). To be specific, rectal temperature wasmaintained at 37° C. and two points of sciatic notch and ankle werepercutaneously stimulated electrically. The distance between thestimulation points was divided by the difference between latencies ininduced electromyogram to give nerve conduction velocity. TABLE 4 dosesciatic nerve conduction velocity test group mg/kg/day m/sec 4 wks afteradministration Diabetes group 0 44.3 ± 1.1  Compound A-2 0.05 46.6 ±1.5  Administered group Compound A-2 0.5 51.9 ± 1.2** Administered groupCompound A-2 5 51.7 ± 1.4** Administered group

[0076] The data was shown by mean±standard error of 7-9 mice per group.Each group was compared to diabetes group by Dunnett's test (**P<0.01).TABLE 5 dose sciatic nerve conduction velocity test group mg/kg/daym/sec 5 wks after administration Diabetes group 0 39.6 ± 1.2  CompoundA-A 0.3 45.2 ± 1.2** Administered group Compound A-4 1 45.9 ± 0.7**Administered group Compound A-4 3 45.3 ± 0.8** Administered group

[0077] The data was shown by mean±standard error of 8-9 mice per group.Each group was compared to diabetes group by Dunnett's test (**P<0.01).

[0078] From the above-mentioned results of Experimental Examples, thecompound A-2 and compound A4 of the present invention increased sciaticnerve conduction velocity of spontaneous diabetic mice.

Experimental Example 3

[0079] Diabetes was induced by intravenous administration ofstreptozotocin (65 mg/kg) to 6week-old male Sprague-Dawley rats.Starting from 16 weeks after the onset of diabetes, a 0.5%hydroxypropylmethylcellulose suspension containing compound A-1 wasorally administered once a day. At 5 weeks from the administration, tailnerve conduction velocity was measured with an induction potential testdevice Neuropack 2, manufactured by Nihon Kohden) according to amodification of the method of Miyoshi (Fukuoka Medical Journal, vol. 62,pp. 588-603 (1971)). To be specific, subcutaneous temperature at thetail was maintained at 37° C. and the tail nerve was percutaneouslystimulated electrically at 2 stimulation points (interval 6 cm). Thedistance between the stimulation points was divided by the differencebetween latencies in induced electromyogram to give nerve conductionvelocity. TABLE 6 tail nerve conduction velocity (m/sec) dose before 5wks after test group mg/kg/day administration administration Controlgroup 0 54.0 ± 0.5 54.4 ± 0.5 Diabetes group 0 46.4 ± 0.5 46.9 ± 0.3Compound A-1 0.3 46.2 ± 0.5 48.3 ± 0.6 Administered group Compound A-1 146.1 ± 0.4  49.4 ± 0.4** Administered group Compound A-1 3 46.0 ± 0.3 50.2 ± 0.5** Administered group

[0080] The data was shown by mean±standard error of 10 rats per group.Each group administered with the compound was compared to diabetes groupby Dunnett's test (**P<0.01).

[0081] From the above-mentioned results of Experimental Example, thecompound A-1 increased tail nerve conduction velocity that had beenlowered by the progression of diabetes, in a dose-dependent manner.

Experimental Example 4

[0082] Diabetes was induced by intravenous administration ofstreptozotocin (65 mg/kg to 5-week-old male Sprague-Dawley rats.Starting from 9 weeks after the onset of diabetes, a 0.5%hydroxypropylmethylcellulose suspension containing compound A-1 wasorally administered once a day. At 9 weeks from the administration,kidney was removed to determine the degree of glomerular disorder andfixed in a 10% neutral-buffered formalin solution. Tissue sections werestained with hematoxylin/eosin. Glomerulus was evaluated according tothe degree of obstruction in 5 stages (0: no obstruction, 1: up to 25%obstruction, 2: up to 50% obstruction, 3: up to 75% obstruction, 4: upto 100% obstruction). Fifty glomeruli were evaluated per sample and thetotal score was used as an index of the degree of glomerular disorder.This operation was done under a single blind condition. TABLE 7 dosetest group mg/kg/day n glomerular disorder score Diabetes group 0 9 90.2± 7.9  Compound A-1 0.3 5 90.8 ± 10.0 Administered group Compound A-1 17 65.7 ± 12.0 Administered group Compound A-1 10 8 55.4 ± 9.2*Administered group

[0083] From the above-mentioned results of Experimental Example, thecompound A-1 of the present invention suppressed glomerular disorder dueto diabetes in a dose-dependent manner.

Experimental Example 5

[0084] Diabetes is induced by intravenous administration ofstreptozotocin (65 mg/kg) to 6week-old male Sprague-Dawley rats.Starting from 2 weeks after the onset of diabetes, a 0.5%hydroxypropylmethylcellulose suspension containing compound A-1 isorally administered once a day. Urine is taken with the passage of timefor 24 hours at several weeks' interval. The amount of urinary albuminexcretion is determined by enzyme immunoassay. In addition, retina isphotographed and examined by counting neogenetic blood vessels. Afterthe completion of the drug administration, the rats are killed and bloodvessels, such as aorta, are taken to make tissue samples. The samplestained with hematoxylin/eosin is observed with an optical microscope toquantitatively determine the degree of tunica intima

[0085] From the above-mentioned Formulation Examples and PharmacologicalExperiments, it is clear that the pharmaceutical agent of the presentinvention is useful for the prophylaxis and treatment of diabeticcomplications, namely, diabetic neuropathy, nephropathy, ophthalmopathy,arteriosclerosis and the like. The action of the drug is long-lastingfor very small doses and a single administration a day is sufficient.

What is claimed is:
 1. A method for the prophylaxis and treatment ofdiabetic ophthalmopathy, comprising administering an effective amount of4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid,an optically active compound thereof or a pharmaceutically acceptablesalt thereof.
 2. A method for the prophylaxis and treatment of diabeticophthalmopathy, comprising administering an effective amount of sodium4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoatedihydrate.
 3. A method for the prophylaxis and treatment of diabeticophthalmopathy, comprising administering an effective amount of(S)-(−)4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid or a pharmaceutically acceptable salt thereof.
 4. A method for theprophylaxis and treatment of diabetic ophthalmopathy, comprisingadministering an effective amount of sodium(S)-(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate.
 5. A method for the prophylaxis and treatment of diabeticarteriosclerosis, comprising administering an effective amount of4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoic acid,an optically active compound thereof or a pharmaceutically acceptablesalt thereof.
 6. A method for the prophylaxis and treatment of diabeticarteriosclerosis, comprising administering an effective amount of sodium4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoatedihydrate.
 7. A method for the prophylaxis and treatment of diabeticarteriosclerosis, comprising administering an effective amount of(S)-(−)4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoicacid or a pharmaceutically acceptable salt thereof.
 8. A method for theprophylaxis and treatment of diabetic arteriosclerosis, comprisingadministering an effective amount of sodium(S)-(−)-4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3,5-dimethylbenzoate2/3 hydrate.
 9. The method of claim 1, wherein the diabeticophthalmopathy is cataract.
 10. The method of claim 1, wherein thediabetic ophthalmopathy is glaucoma.
 11. The method of claim 1, whereinthe diabetic ophthalmopathy is retinopathy.
 12. The method of claim 1,wherein the diabetic ophthalmopathy is iritis.
 13. The method of claim2, wherein the diabetic ophthalmopathy is cataract.
 14. The method ofclaim 2, wherein the diabetic ophthalmopathy is glaucoma.
 15. The methodof claim 2, wherein the diabetic ophthalmopathy is retinopathy.
 16. Themethod of claim 2, wherein the diabetic ophthalmopathy is iritis. 17.The method of claim 3, wherein the diabetic ophthalmopathy is cataract.18. The method of claim 3, wherein the diabetic ophthalmopathy isglaucoma.
 19. The method of claim 3, wherein the diabetic ophthalmopathyis retinopathy.
 20. The method of claim 3, wherein the diabeticophthalmopathy is iritis.
 21. The method of claim 4, wherein thediabetic ophthalmopathy is cataract.
 22. The method of claim 4, whereinthe diabetic ophthalmopathy is glaucoma.
 23. The method of claim 4,wherein the diabetic ophthalmopathy is retinopathy.
 24. The method ofclaim 4, wherein the diabetic ophthalmopathy is iritis.